Preparation of phenylmalonic acid



Unit

PREPARATION OF PHENYLMALONIC ACID No Drawing. Application June 11, 1954 Serial No. 436,241

3 Claims. (Cl. 260-515) This invention relates generally to an improved method for the preparation of phenylmalonic acid and its derivatives, particularly diesters of phenylmalonic acid.

There are a number of processes by which phenylmalonic acid and its diesters such as dimethyl and diethyl esters can be prepared. The best of these methods and the ones in commercial use start with benzyl chloride which is converted to benzyl cyanide and this compound is then converted to phenylacetic acid and ethylphenylacetate. By one route, the ethyl phenylacetate is converted with diethyl carbonate and sodium ethoxide to diethyl phenylma1onate.' An alternate method consists of treating the ethyl phenylacetate with diethyl oxalate and sodium ethoxide to give diethyl phenyloxalylacetate which is then decarboxylated to give diethyl phenylmalonate. These methods are long, involved and expensive in addition to requiring the isolation of a number of intermediates. However, this new and improved process for phenylmalonic acid and dimethyl or diethyl phenylmalonate avoids all of the difiiculties associated with the above processes.

In accordance with this improved method, dimethyl phenylmalonate can be prepared in one reactor from chlorobenzene, dispersed sodium, toluene, carbon dioxide, hydrochloric acid and methanol. bines economy with simplicity of plant design.

It has now been discovered that phenylmalonic acid and its diester derivatives can be prepared in good yields and selectivities directly from chlorobenzene. The chlorobenzene is initially reacted with finely dispersed sodium in toluene. This reaction gives a substantially quantitative yield of phenylsodium. The phenylsodium is directly and immediately thereafter quantitatively converted to benzylsodium by the metalation of an equimolar portion of the toluene reaction medium. The resulting benzylsodium is carbonated under selective and critical conditions to give a relatively high yield of phenylmalonic acid with only a minor portion of phenylacetic acid. Theacidic-components of the reaction mixture can then be esterified to produce the methyl esters which are easily separated by distillation. If desired, the acids can be separated first andythe pure phenylmalonic acid esterified to give the diester. This esterification is unusually difiicult because of the great tendency of the phenylmalonic acid towardsdecarboxylation. For this reason, the conditions' are extremely critical and comprise an integral part of the new process since esterification of this diacid has not previously been feasible.

Furthermore, certain conditions are essential for formation of maximum yields of. phenylmalonic acid. It is initially necessary to prepare phenylsodium from chlorobenzene and finely dispersed sodium. These materials are, reacted, together at atemperature of Q to 40 C. and

SWSPMM This new process compreferably about 25 to 30 C. in a reaction medium consisting solely of toluene. This results in the quantitative formation of phenylsodium. The reaction mixture containing the phenylsodium is refluxed for a period of about two hours. These reactions give an essentially quantitative yield (95 to 99%) of benzylsodium from the chloro- The reaction is as follows:

benzene.

Carbonation of benzylsodium gives, as the initial carbonation product, the sodium salt of phenylacetic acid according to the following equation:

C H CH Na+CO C H CH COONa-|-C H CH While it had been previously reported that some"- phenylmalonic acid is thus formed during gaseous carbonation of benzylsodium at low temperatures, no attempt had previously beenmade to control carbonation conditions so that the desired phenylmalonic acid Wasproduced as the major product of the total reaction.

At carbonation temperatures from 30 to 60 C. and under critical conditions, phenylmalonic acid is produced in a yield of about with an accompanying 25% yield of phenylacetic acid. The disodium salt of phenyli malonic acid is produced according to the following reaction:

CaH GHgNa+CaH5CHrC0ONa COHSCHCOONB-i-CoHsCH:

CaHsOHCOONa 002 GoHtCI-HCOONa);

It was found that the yield of phenylmalonic acid could not be increased much above 70% regardless of carbonation temperature or rate. that carbonation at high temperatures decreased the yield of phenylacetic acid, but all of the sodium and chlorobenzene could not be accounted for in isolated products.

This apparent anomaly is explainable if a continuing metalation reaction is assumed. This, if the alpha carbon atom is metalated further by unreacted benzylsodium in the presence of carbon dioxide, there would be produced the trisodium salt of phenyltricarboxymethane, C H C(COONa) On neutralization with hydrochloric acid, the phenyltricarboxymethane would be expected to decarboxylate to phenylmalonic acid. Actually, in the experiments where a low yieldwas obtained,

considerable carbon dioxide was evolved during neutral tion an attrition apparatus, such as a ball mill or pebble I mill, can be employed. This eliminates the necessity for an excess of sodium, since the appropriate stoichiometric amount of sodium is quite satisfactory. It is necessary to have the toluene present in considerable excess for the best ultimate yields. The presence of other hydrocarbon diluents, such as benzene, gives reduced yields. Hence, the toluene is conveniently em-' ployed as the reaction medium for the reaction of chlorobenzene with sodium. An inert atmosphere should, also Pi ated Apr 7.195?

It was evident though,

It is preferably verted to benzylsodium by reaction with the toluene at reflux temperature (110 C.).

In order to obtain selective and high yields of the de-- sired phenylmalonic acid with only minor amounts of phenylacetic acid, it is necessary to add gaseous carbon dioxide to the benzylsodium suspension over a period of several hours at 30 to 60 C. This temperatureis important to obtain the best product balance based on chlorobenzene. There is obtained a 70% yield of phenylmalonic acid along with 25% of phenylacetic acid. Efficient stirring is necessary throughout the entire reaction period to insure mixing of gas, liquid, and solid phases, and to permit controlled reaction rate. After carbonation, any excess sodium and/or organosodium compounds are decomposed and the free acids esterified directly or recovered by precipitation.

Treatment of the reaction mixture containing the sodium salts of the acids directly with 15 to 20 parts of methanol to one part of acid and hydrogen chloride in excess, followed by a heating period of about five hours at 60 C. gives a mixture of a major proportion of dimethyl phenylmalonate and a minor proportion of methyl phcnylacetate in the ratio of about 3 to 1. This mixture is easily separated by distillation. If desired, the free acids may be separated before esterification by their solubility differences in benzene and the phenylmalonic acid esterified separately. The yield of dimethyl phenylmalonate, based on phenylmalonic acid, is 95%; while the over-all yield, based on chlorobenzene, is 65-70%. Similar yields of the diethyl ester are obtained by employing absolute ethanol under similar reaction conditions.

The invention will be more fully described by the following examples, but it is not intended to be limited specifically thereto.

EXAMPLE 1 The sodium dispersions are stable suspensions of sodium in inert hydrocarbon media with particles ranging in size from submicron to 25 microns in diameter. Methods of preparation, properties, and uses of 50% sodium dispersions are well known to the art. In general, less concentrated dispersions are better for this process.

Preparation of the 15 sodium dispersions may be accomplished in either of several ways, as by formation of a 50:50 dispersion of sodium and liquid medium in small equipment, followed by transfer to a large reactor for dilution to the 15% sodium concentration (by weight), or or by dispersion of the sodium at the desired 15% sodium concentration in a vessel large enough to handle subsequent reactions. The dispersion may then be diluted with the desired media in the same reactor or after transfer to the larger reactor, as in the second method. An inert atmosphere should be maintained at all times to avoid deactivation of the sodium or hydrolysis of the phenylsodium.

To 54 grams (2.34 gram-atoms) of finely dispersed sodium (nitrogen atmosphere, less than 25-micron particle size average) suspended in 275 grams of toluene in a three-necked flask at 25 to 30 C. is added slowly, with gentle agitation, a mixture of 112.5 grams (1 mole) of chlorobenzene and 100 grams of toluene. Initiation of reaction usually occurs 1 to 5 minutes after addition of thefirst to 25 ml. of the chlorobenzene-toluene mixture and is characterized by an increasingly rapid temperature rise, plus the appearance of the black phenylsodium particles. The temperature of the reacting mixture should not be allowed to exceed 40 C. The rate of addition and cooling should be regulated so that the formation of the phenylsodium will be complete in 20 to 30 minutes.

The resulting toluene suspension of phenylsodium is refluxed for two hours. Carbonation is then effected by the slow introduction of gaseous carbon dioxide into the total reaction mixture. In some cases approximately one-half of the theoretical quantity of carbon dioxide was added rapidly to the benzylsodium suspension. After this addition, the reaction mixture was allowed to stir for a 30 to 60 minute period. Although this procedure should serve to convert one-half of the benzylsodium to sodium phenylacetate and the stirring period that followed would allow for metalation of the sodium phenylacetate-by the remainder of the benzylsodium, this technique did not materially increase the yield of phenylmalonic acid (see Table I). However, the carbonation time was reduced and a tendency toward a better product balance was observed when this procedurewas used.

When carbonation was complete, the resulting slurry was added to water and steam for decomposition. When the excess sodium had been destroyed, the waterlayer was separated and treated with decolorizing carbon. The resulting solution of salts was cooled to 0 C. and neutralized with hydrochloric acid. In the presence of phenylacetic acid and sodium chloride, some phenylmalonic acid is carried down. The phenylacetic acid may be re moved by extraction with benzene. Phenylmalonic acid can be separated from the water and salt by extraction with ethyl ether. Evaporation of the ether under vacuum gives phenylmalonic acid (melting point, 150 to 152 G). Since phenylmalonic acid readily decarboxylates to phenylacetic acid, some care should be takeniin neutralization and evaporation steps to avoid temperatures above 30 C. to insure maximum yields.

EXAMPLE 2 In all of the experiments listed in Table I, gaseous carbon dioxide was introduced to the suspension of benzylsodium. The rate of carbonation of the surface of the Gaseous carbonation under controlled conditions of hen-- zylsodium at 30 to 60 C. (Experiment 5, Table I) gives a 67% yield of phenylmalonic acid along with 27% phenylacetic acid.

Table l Carbonation Phenyl- Phenyl- Expt. acetic malonlc Total No. acid acid yield Remark:

Temp., Time, yield, yield,

0. min. percent percent 1-- 30 60 60 24 84 2- 5 100 43 48 91 3"-.- 30 195 16. 3 67. 3 83; 6 4-..-.. 40 30 16.3 67.6 83.0 Approx. one-hal therat-teal uantlty 002 adde tam mtn.;l gabonaftlfin compo rap in 10 min. y 5.....- 30-00 90 27.5 67.3 94.8 Approx. one-halftimeoretlcal quantity CO1 added in 10 mtn.; stirred 30 mln.; carbonation completed slowly msomln. 6-. 50- 60 240 5.2 72.1 77.3 7- 70- 240 3.7 74.0 77.7 8"--. -110 120 9.0 63.4 72.4 9---.. -100 240 5.1 69.8 74.9

EXAMPLE 3 Dimethyl phenylmalonate may be prepared, in yields up to 94%, by heating a benzene-methanolic solution of phenylmalonic acid and hydrogen chloride at 60 C. for 5 hours. The results, listed in Table II, show that a large excess of methanol (at least to 1 mole ratio) is required for maximum yields. Concentrated sulfuric acid can also be used as an esterification catalyst. Yields of ester up to 87% are possible if a 3 to 1 mole ratio of sulfuric acid to phenylmalonic acid is used. It is also important to allow the reaction mixture (phenylmalonic acid, methanol, sulfuric acid, benzene) to stir at room temperature (about 25 C.) for several hours before raising the temperature to 65 C. Reaction temperatures below 65 C. give slightly lower yields of ester.

The diethyl ester of phenylmalonic acid may be prepared (85% yield) by treatment of the acid with absolute ethyl alcohol and anhydrous hydrogen chloride in benzene solution for 5 hours at 60 C.

EXAMPLE 4 It is also possible to prepare dimethyl phenylmalonate in a stepwise, one-reactor process, from sodium, chlorobenzene, toluene, carbon dioxide, methanol, and hydrogen chloride. After carbonation of benzylsodium at 30 to 50 C. the reaction mixture containing disodium phenylmalonate, sodium phenylacetate, and a small amount of free sodium is treated with a large excess of methanol (10 parts methanol to 1 part phenylmalonic acid). When this addition is complete, anhydrous hydrogen chloride may be passed through the resulting thick slurry in order to neutralize the sodium salts of the organic acids and the sodium methoxide formed from the free sodium. When neutralization is complete, the reaction mixture is heated at 60 C. for 5 hours. Anhy- What is claimed is:

1. In a process in which the sodium salt of phenylmalonic acid is prepared by carbonation of benzyl sodium, the improvement which comprises the steps of reacting finely dispersed sodium having an average particle size of less than 25 microns and chlorobenzene in a reaction medium consisting solely of toluene at a temperature of about 0 to C., refluxing the total reaction mixture to produce benzyl sodium, and immediately thereafter contacting the mixture with gaseous carbon dioxide at a tem perature of about 30 to 60 C. in an amount substantially less than theoretically required to carbonate all of the benzyl sodium in said mixture, and then contacting the resulting partially carbonated mixture with an amount of carbon dioxide sutficient to produce a carbonated mixture comprising a major proportion of the disodium salt of phenylmalonic acid and a minor proportion of the sodium salt of phenylacetic acid.

2. The process of claim 1 wherein said reaction between the finely dispersed sodium and the chlorobenzene is carried out at a temperature of about 25 to 30 C.

3. In a process in which the sodium salt of phenylmalonic acid is prepared by carbonation of benzyl sodium, the improvement which comprises the steps of reacting finely dispersed sodium having an average particle size of less than about 25 microns and chlorobenzene in a reaction medium consisting solely of toluene at a temperature of about 25 to 30 C., refluxing the total reaction mixture to produce benzyl sodium, and immedi ately thereafter contacting the mixture with gaseous carbon dioxide at a temperature about 30 to 60 C. in an amount of about of that theoretically required to carbonate all of the benzyl sodium in said mixture, and contacting the resulting partially carbonated mixture with an amount of gaseous carbon dioxide at 30 to C. suflicient to produce a carbonated mixture comprising a major proportion of the disodium salt of phenylmalonic Table II Phenyl- Absolute Dimethyl Methyl Expt malonic meth- Temp., Time, phenylphenyl- Total No. acid, anoL 0. min. malonate acetate yield Remarks moles moles yield, yield,

percent percent 1 0. 11 1.85 330 93. 1 93.1 Anhydrous H01 bubbled through reaction mixture during heating.

2 0. 50 4. 60 270 35.4 52.3 87. 7 Anhydrous H01 bubbled through reaction mixture during heating; low yield due to a decrease in the methanolpbeuylmalonic acid ratio from the usual 10/1 to ELL 3 5. 56 60 300 94. 4 94.4 Anhydrous H01 bubbled t rough reaction mixture during heating.

4 0. 33 6. 66 60 b 1, 080 S0. 0 19. 7 99. 7 1 mole H1804 catalyst.

6 0. 20 8.0 60 d 1, 320 85. 9 85. 9 0.6 mole H2804 catalyst; increase in methanol fillnleinylmalouic acid ratio from usual 10/1 to I Reagent grade benzene, twice the volume of methanol, also used. b Includes initial 2-hour stirring at 39 C. e Includes initial l-hour stirring at 31 0. 4 Includes initial 2-hour stirring at 31 C.

drous hydrogen chloride is passed through the solution 0 acid and a minor proportion of the sodium salt of phenylduring the entire heating period. At the end of this time, the addition of water will serve to remove the sodium chloride (from original chlorobenzene reaction, from excess sodium, and from esterification). The benzene (present as a result of the phenylsodium metalation reaction) and toluene can be removed by flash distillation. Dimethyl phenylmalonate (boiling point 148 to 152 C./ 10 mm.; melting point, 47 to 49 C.) and methyl phenylacetate (boiling point, to C./ 10 mm.) are then separated by vacuum distillation.

Similarly, the diethyl esters can be prepared by the substitution of ethanol for methanol.

acetic acid.

References Cited in the file of this patent UNITED STATES PATENTS Hickinbottom: Reactions of Organic Compounds, p. 100 (1948). 

1. IN A PROCESS IN WHICH THE SODIUM SALT OF PHENYLMALONIC ACID IS PREPARED BY CARBONATION OF BENZYL SODIUM, THE IMPROVEMENT WHICH COMPRISES THE STEPS OF REACTING FINELY DISPERSED SODIUM HAVING AN AVERAGE PARTICLE SIZE OF LESS THAN 25 MICRONS AND CHLOROBENZENE IN A REACTION MEDIUM CONSISTING SOLELY OF TOLUENE AT A TEMPERATURE OF ABOUT 0* TO 40* C,. REFLUXING THE TOTAL REACTION MIXTURE TO PRODUCE BENZYL SODIUM, AND IMMEDIATELY THERAFTER CONTACTING THE MIXTURE WITH GASEOUS CARBON DIOXIDE AT A TEMPERATURE OF ABOUT 30* TO 60* C. IN AN AMOUNT SUBSTANTIALLY LESS THAN THEORETICALLY REQUIRED TO CARBONATE ALL OF THE BENZYL SODIUM IN SAID MIXTURE, AND THEN CONTACTING THE RESULTING PARTIALLY CARBONATED MIXTURE WITH AN AMOUNT OF CARBON DIOXIDE SUFFICIENT TO PRODUCE A CARBONATED MIXTURE COMPRISING A MAJOR PROPORTION OF THE DISODIUM SALT OF PHENYLMALONIC ACID AND A MINOT PROPORTION OF THE SODIUM SALT OF PHENYLACETIC ACID. 